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1.
Russ J Gen Chem ; 87(6): 1264-1274, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-32288469

RESUMO

A series of substituted and fused heterocyclic derivatives 2-17 were synthesized using 3,5-bis(4-methoxybenzylidene)-1-propylpiperidin-4-one (1) as starting material. Treatment of 1 with malononitrile or semicarbazide afforded compounds 2 and 3, respectively. Condensation of 1 with ethyl cyanoacetate afforded naphthyridine-3-carbonitrile derivative 4, which reacted with phosphorus pentachloride and phosphoryl chloride to give chloro derivative 5. Treatment of 5 with thiosemicarbazide afforded compound 6. The reaction of 1 with malononitrile gave cyano aminopyrane derivative 7 which was condensed with pyromellitic dianhydride, phthalic anhydride, succinic anhydride, or morpholine in glacial acetic acid to obtain imide derivatives 8-11. Additionally, the reaction of 7 with aromatic aldehydes gave derivatives 12a-12c. Acetylation of 7 with acetic anhydride in boiling acetic acid gave N-acetyl derivative 13 which was cyclized to pyridine derivative 14 by refluxing in dioxane in the presence of triethylamine. Treatment of 7 with hydrazine hydrate gave pyrazolo derivative 15. Finally, the reaction of 7 with triethyl orthoformate in the presence of acetic anhydride gave formimidate 16 which was treated with hydrazine hydrate to form N-amino derivative 17. Some of the synthesized compounds were examined in vitro for their antitumor activity against HepG-2, PC-3, and HCT-116 human carcinoma cell lines using MTT assay.

2.
Chem Res Toxicol ; 14(4): 398-408, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11304128

RESUMO

A structure-activity study on the quinone/quinone methide chemistry of a series of 3',4'-dihydroxyflavonoids was performed. Using the glutathione trapping method followed by HPLC, (1)H NMR, MALDI-TOF, and LC/MS analysis to identify the glutathionyl adducts, the chemical behavior of the quinones/quinone methides of the different flavonoids could be deduced. The nature and type of mono- and diglutathionyl adducts formed from quercetin, taxifolin, luteolin, fisetin, and 3,3',4'-trihydroxyflavone show how several structural elements influence the quinone/quinone methide chemistry of flavonoids. In line with previous findings, glutathionyl adduct formation for quercetin occurs at positions C6 and C8 of the A ring, due to the involvement of quinone methide-type intermediates. Elimination of the possibilities for efficient quinone methide formation by (i) the absence of the C3-OH group (luteolin), (ii) the absence of the C2=C3 double bond (taxifolin), or (iii) the absence of the C5-OH group (3,3',4'-trihydroxyflavone) results in glutathionyl adduct formation at the B ring due to involvement of the o-quinone isomer of the oxidized flavonoid. The extent of di- versus monoglutathionyl adduct formation was shown to depend on the ease of oxidation of the monoadduct as compared to the parent flavonoid. Finally, unexpected results obtained with fisetin provide new insight into the quinone/quinone methide chemistry of flavonoids. The regioselectivity and nature of the quinone adducts that formed appear to be dependent on pH. At pH values above the pK(a) for quinone protonation, glutathionyl adduct formation proceeds at the A or B ring following expected quinone/quinone methide isomerization patterns. However, decreasing the pH below this pK(a) results in a competing pathway in which glutathionyl adduct formation occurs in the C ring of the flavonoid, which is preceded by protonation of the quinone and accompanied by H(2)O adduct formation, also in the C ring of the flavonoid. All together, the data presented in this study confirm that quinone/quinone methide chemistry can be far from straightforward, but the study provides significant new data revealing an important pH dependence for the chemical behavior of this important class of electrophiles.


Assuntos
Benzoquinonas/química , Flavonoides/química , Indolquinonas , Indóis/química , Quinonas/química , Cromatografia Líquida de Alta Pressão , Glutationa/química , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Relação Estrutura-Atividade
3.
Transplantation ; 71(4): 552-60, 2001 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-11258435

RESUMO

BACKGROUND: The application of gene therapy to prevent allograft rejection requires the development of noninflammatory vectors. We have therefore investigated the use of a nonviral system, transferrin-mediated lipofection, to transfer genes into the cornea with the aim of preventing corneal graft rejection. METHODS: Rabbit and human corneas were cultured ex vivo and transfected with either lipofection alone or in conjunction with transferrin. The efficiency of transfection, localization, and kinetics of marker gene expression were determined. Strategies to increase gene expression, using chloroquine and EDTA, were investigated. In addition to a marker gene, a gene construct encoding viral interleukin 10 (vIL-10) was transfected and its functional effects were examined in vitro. RESULTS: Transferrin, liposome, and DNA were demonstrated to interact with each other, forming a complex. This complex was found to deliver genes selectively to the endothelium of corneas resulting in gene expression. Treatment of corneas with chloroquine and EDTA increased the transfection efficiency eight-fold and threefold, respectively. We also demonstrated that constructs encoding vIL-10 could be delivered to the endothelium. Secreted vIL-10 was shown to be functionally active by inhibition of a mixed lymphocyte reaction. CONCLUSIONS: Our data indicate that transferrin-mediated lipofection is a comparatively efficient nonviral method for delivering genes to the corneal endothelium. Its potential for use in preventing graft rejection is shown by the ability of this system to induce vIL-10 expression at secreted levels high enough to be functional.


Assuntos
Endotélio Corneano/metabolismo , Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Receptores da Transferrina/genética , Animais , Cloroquina/farmacologia , Citomegalovirus/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-10/genética , Regiões Promotoras Genéticas , Coelhos , Fatores de Tempo , Transfecção , beta-Galactosidase/genética
5.
Am J Respir Crit Care Med ; 162(4 Pt 2): S194-200, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11029394

RESUMO

Gene transfer to the corneal endothelium has potential for modulating rejection of corneal grafts. It can also serve as a convenient and useful model for gene therapy of other organs. In this article we review the work carried out in our laboratory using both viral and nonviral vectors to obtain gene expression in the cornea.


Assuntos
Endotélio Corneano/patologia , Técnicas de Transferência de Genes , Rejeição de Enxerto/terapia , Adenoviridae/genética , Animais , Vetores Genéticos , Rejeição de Enxerto/genética , Rejeição de Enxerto/patologia , Humanos , Tolerância ao Transplante/genética
6.
Arch Biochem Biophys ; 378(2): 224-33, 2000 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-10860540

RESUMO

The oxidation of quercetin by horseradish peroxidase/H(2)O(2) was studied in the absence but especially also in the presence of glutathione (GSH). HPLC analysis of the reaction products formed in the absence of GSH revealed formation of at least 20 different products, a result in line with other studies reporting the peroxidase-mediated oxidation of flavonoids. In the presence of GSH, however, these products were no longer observed and formation of two major new products was detected. (1)H NMR identified these two products as 6-glutathionylquercetin and 8-glutathionylquercetin, representing glutathione adducts originating from glutathione conjugation at the A ring instead of at the B ring of quercetin. Glutathione addition at positions 6 and 8 of the A ring can best be explained by taking into consideration a further oxidation of the quercetin semiquinone, initially formed by the HRP-mediated one-electron oxidation, to give the o-quinone, followed by the isomerization of the o-quinone to its p-quinone methide isomer. All together, the results of the present study provide evidence for a reaction chemistry of quercetin semiquinones with horseradish peroxidase/H(2)O(2) and GSH ultimately leading to adduct formation instead of to preferential GSH-mediated chemical reduction to regenerate the parent flavonoid.


Assuntos
Glutationa/metabolismo , Peroxidase do Rábano Silvestre/metabolismo , Peróxido de Hidrogênio/metabolismo , Quercetina/análogos & derivados , Quercetina/química , Quercetina/metabolismo , Cromatografia Líquida de Alta Pressão , Elétrons , Flavonoides/química , Flavonoides/metabolismo , Espectroscopia de Ressonância Magnética , Fatores de Tempo
7.
Amino Acids ; 16(3-4): 425-40, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10399025

RESUMO

In search for more potent, particularly less ulcerogenic gastritis that hopefully replace the universal NSAID "Diclofenac", (2-[(2,6-dichlorophenyl)amino]-phenylacetic acid, C.A.S. 15307-86-5), twelve new non-proteinogenic amino acid conjugates of the drug, namely that of sarcosine, beta-alanine, D-leucine and D-phenylalanine, were synthesized and biologically screened for their anti-inflammatory, analgesic and ulcerogenic activity in rats. "Diclofenac" amino acid esters (IIa-d), were synthesized via the corresponding HOSu or HOBt active esters. Alkaline hydrolysis (NaOH) followed by acidification (KHSO4) or thioamide formation (Lawsson's Reagent, C.A.S. 19172-47-5), afforded the corresponding free acids IIIa-d or the thioamides IVa-d respectively. Interestingly, in contrary to the parent "Diclofenac", the synthesized candidates (except IIId), were entirely nonulcerogenic in rats. Further, they considerably retained a generalized anti-phlogistic activity. The major "Diclofenac" irritating gastric side effect was thus eliminated. Particularly, the sarcosine conjugate IIa and its thiomimic IVa exhibit promising therapeutic perspectives.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Diclofenaco/síntese química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/toxicidade , Diclofenaco/química , Diclofenaco/farmacologia , Diclofenaco/toxicidade , Ratos , Sarcosina/química , Sarcosina/farmacologia , beta-Alanina/química , beta-Alanina/farmacologia
8.
Acta Pol Pharm ; 55(3): 211-21, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9735702

RESUMO

New proteinogenic amino acids conjugates of 2-[2,6-dichlorophenyl-1-amino]phenyl acetic acid "Diclofenac", [I] were synthesized. Glycine methyl ester and L-methionine ethyl ester were coupled with [I] via the active ester method to give the corresponding 2-[2,6-dichlorophenyl-1-amino]benzyl carboxy N-amino acid ester of the type [IIa, b], respectively, which were hydrolyzed in alkaline medium to yield the free amino acids [IIIa, b]. Condensation of IIIa with glycine methyl ester using a modified classical carbodiimide (DCCI) method gave the corresponding, "Diclofenac" glycylglycine methyl ester [IVa]. Hydrolysis of compounds IVa gives the corresponding acid Va. Thionation of compounds IIb and IVa by reaction with Lewesson's Reagent (LR), afforded the corresponding thio-analogues (VIa and IVb). Interestingly, while retaining considerable comparative anti-phlogistic activity (anti-inflammatory and analgesic), the synthesized candidates proved to be practically nonulcerogenic in rats.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Diclofenaco/síntese química , Diclofenaco/farmacologia , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Diclofenaco/análogos & derivados , Masculino , Ratos , Úlcera Gástrica/induzido quimicamente , Relação Estrutura-Atividade
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